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NUMERICAL ABNORMALITIES
IN
CHROMOSOMES
DR BETTY JOHN
FRCOG, MRCOG, MD, DGO
CONSULTANT GYNAECOLOGIST
ZULEKHA HOSPITAL SHARJAH
Numerical and Structural Abnormalities Of Chromosomes
�Chromosomal abnormalities or aberration is a missing ,
extra or irregular portion of chromosomal DNA .
�They usually occur as a result of errors in meiotic / mitotic
cell division.
�They can be inherited from a parent or be “ de novo “
TYPES OF CHROMOMOSOMAL
ABNORMALITIES
There are 2 main types of chromosomal abnormalities :
� NUMERICAL
� STRUCTURAL
NUMERICAL ABNORMALITIES
�Known as aneuploidy (abnormal number chromosomes ).
�Usually caused by failure of chromosome division (NON -
DISJUNCTION) which results in cells with an extra
chromosome or deficient chromosome.
�The causes of non – disjunction are :-
�Aging effect
� Radiation
� Delayed fertilization after ovulation.
Common Numerical Abnormalities
�Triploidy , Trisomy } Autosomal Chromosomes
�Monosomy } Sex chromosomes
�Mosaicism
Most aneuplodies are incompatible with life
resulting in spontaneous abortions except for
trisomy 21 , 13 and 18 and monosomy X which can
result in viable pregnancies.
Most frequent numerical anomalies in liveborn
Autosomes
Down syndrome (trisomy 21: 47,XX,+21)
Edwards syndrome (trisomy 18: 47,XX,+18)
Patau syndrome (trisomy 13: 47,XX+13)
Sex chromosomes
Turner syndrome 45,X
Klinefelter syndrome 47,XXY
All chromosomes
Triploidy (69 chromosomes)
Chromosomal findings in early miscarriages
40% apparently normal
60% abnormal:
�Trisomy (47 chromosomes – one extra) 30%
�45,X (45 chromosomes – one missing) 10%
�Triploidy (69 chromosomes – three sets) 10%
�Tetraploidy (92 chromosomes – four sets) 5%
�Other chromosome anomalies 5%
(e.g. structural anomalies)
TRIPLOIDY� Three copies of each chromosome making a total of 69
chromosomes.
� It occurs in 1 to 2 % of all pregnancies.
� Most Triploid die early in preg - spontaneous
miscarriages(~10%).Almost all other babies die later or are
stillborn. Live born very rare.
� It is not hereditary.
� There are no specific risk factors.
� Not more common in older mothers.
� No increased risk in future pregnancies
TRIPLOIDY
Failure of meiotic division -2 N gamete + haploid gamete of
other parent= Triploid Zygote (69 XXX ,69 XXY ,69 XYY)
TRISOMY
All trisomies ( trisomy 21 , 13 and 18 ) could be due
to the following three causes :-
�NONDISJUNCTION
�TRANSLOCATION
�MOSAICISM
NON- DISJUNCTION ERROR
� In either mitosis or meiosis .
� If a meiotic error produces a gamete with 2
copies of an A chromosome , fertilization with a
normal gamete will result in trisomy for the A
chromosome.
�Non -disjunction often occurs in the maternal
oocyte , the incidence of which increases with
maternal age.
In meiosis 1 , a
pair of
homologous
chromosomes
fail to
separate 46 /2= 23 ideally but non-
disjunction causes
Cause 2 : Translocation : Reciprocal and Robertsonian
�Is usually an exchange of genetic
material between non-homologous
chromosomes
�Since the translocation is balanced and
there is even exchange of material with
no genetic information extra or missing ,
persons are healthy ( 46 chr )
� 6 % can present as autism , intellectual
disability or with congenital anomalies.
RECIPROCAL TRANSLOCATION Occur due to errors in meiosis
For example : 46 , XY, t ( 5 ; 10 ) STRUCTURAL ABNORMALITY ALSO
Unbalanced Translocation
A person with a unbalanced
translocation has an
increased risk of creating
gametes with unbalanced
chromosomes
Unequal exchange = extra or
missing chromosomes : 1 to 2 %
chance of trisomic fetus
Others will be carrier and normal
offspring
Robertsonian translocation
Two long arms of acrocentric
chromosomes ( 14 and 21 ) join at the
centromere with loss of short arms,
producing balanced two copies of all major
chromosomal arms and essential genes.
The acrocentric chromosomes that are
lost ( therefore 45 chr ) do not have much
important genetic material .
Carriers of this translocation have a
5 % of having a child with trisomy 21
due to inheritance of a long arm of
chromosome 21.
45 , XX , t ( 14 ;21 ) balanced carrier
Cause 3 : MOSAICISM
• Mosaic : When an individual has two or more cell populations
with a different chromosomal make up .
• Results when some of the cells in the body are normal and other
cells have a trisomic or monosomic complement eg : trisomy 21
( 46 XX / 47 XX + 21 ) ( 45% /55%)
Some chromosomal anomalies can happen after conception like
mosaicism. This can result from
1. non –disjunction event during an early mitotic cell division in a
normal embryo or
2 . A trisomic embryo undergoes non –disjunction and some of the
cells revert to a normal chromosomal rearrangement.
Because normal cells are also present in an mosiac ,the
clinical effect may be less severe.
TRISOMY 21- DOWNS
• The incidence is 1 in 700 live births.
• Three causes of trisomy 21 are :
� Non –disjunction : 47 , XY + 21 ( 92 to 95 % of cases )
� Translocation : 4.8 % of cases ( most of the cases are
sporadic ( de novo ) , 1/3 rd of the cases the parents are
carriers )
�Mosaics : 46 XX / 47 XX + 21 ( 2.7 % of the cases)
Trisomy 18 (Edward syndrome)
�1:7500 in liveborn
and more common in
abortion and stillbirth
�Severe mental
retardation and
multiple structural
anomalies
Trisomy 13((((Patau syndrome))))• 1:20,000 in liveborn
and more common in abortion and stillbirth
• Severe structural anomalies lead to death in one month
Recurrence risk of trisomies
� Karyotyping of the affected child will show the cause of trisomy .
( non-disjunction / unbalanced translocation / mosaicism )
� KARYOTYPING OF BOTH THE PARENTS if required.
� If there is no translocation or mosaicism detected in the affected
child there is no need to test parental karyotype
� If there is no translocation in the affected child , the risk of another
child with trisomy is 1% increase above the age related risk.
Recurrence risk of trisomies
� If balanced translocation is detected in the parents , then the
recurrence risk is 1 % in male carriers and 12 % in female carriers.
� In a parent having a balanced translocation between
chromosomes 21 : 21 , the recurrence risk is 100 % .
� If the translocation in the affected child is not inherited ( de novo ) ,
then the parents have a less than 1 % risk of having another
affected child with Downs syndrome.
Recurrence risk of trisomies
� The risk of recurrence for a mosiac pattern is also 1 % above the
age related risk.
� In cases where translocation or mosaic pattern is detected in
parents prenatal invasive testing is MANDATORY .
� There is no increased risk in second degree relatives , unless caused
by unbalanced translocation in the index case.
But routine screening as done for all pregnancies should be done
(Nuchal translucency and 11 to 14 week scan , blood screening and
detailed anomaly scan )
RECURRENCE RISK OF DOWNS SYNDROME
CHROMOSOMAL CONSTITUTION RISK TO OFFSPRING
AFFECTED CHILD FATHER MOTHER
TRISOMY 21 N N MOTHER < 30 YRS 2-3%
IN PRESENT PREG
MOTHER > 30 YRS, MOTHER`S AGE +1%
HAD BABY WITH DOWNS
BEFORE AGE 30
MOTHER >30 YRS, MOTHER`S AGE
HAD BABY WITH DOWNS
AFTER 30 YRS
RECURRENCE RISK OF DOWNS SYNDROME
CHROMOSOMAL CONSTITUTION RISK TO OFFSPRING
AFFECTED CHILD FATHER MOTHER
TRANSLOCATION
14/21, 15/21,13/21,21/22 N N <1%
N C 12%
C N 2- 3%
TRANSLOCATION 21 / 21 100%
MOSAIC N N 2-3%
Sex chromosome abnormalities ( aneuplodies )
� Sex chromosome abnormalities are less severe in their effects
because all but one of the X chromosome gets inactivated because
of the Lyon hypothesis ( Barr body ) and the number of genes on the
Y chromosome are limited.
� Cause of sex chromosome aneuplodies are non-disjunction errors
during meiosis .
However pre-nantal invasive testing should be done.
� Recurrence risk in sex chromosome aneuploidies is very low.
TRIPLE XXX Syndrome
�Often goes undetected throughout life .
�They are often taller than normal and may have learning difficulties
�Fully fertile and generally have chromosomally normal children
47, XXX
TURNER SYNDROME ( MONOSOMY X ,45 XO)
� 45 X karyotype
� Only monosomy compatible with life
� Live born females are usually mosaics ( 45 ,X / 46 XX 45 , X / 46, XY)
Pure 45 X is often lethal.
� Cause:Occurs due to loss of the paternal X chromosome
Nondisjunction in male gamete
Structural abnormalities of X chromosome
One X chromosome is missing
Mitotic nondisjunction
� Phenotype is highly variable in mosaics .
� This abnormality is unrelated to maternal age.
47 , XYY
�Patients are clinically
indistinguishable from 46 XY.
�XYY often goes undetected
throughout life.
�XYY affects 1 in 1000 live
births and is the failure of
paternal meiosis.
�Characteristics include tall
structure , normal intelligence
and normal fertility
KLINEFELTER’S SYNDROME - 47 , XXY
Have 47 chromosomes (XXY) & a sex
chromatin Barr body or 48(XXXY);
more the number of X more the
chances of mental impairment.
Cause: 50 % are due to meiosis 1
error in the father
Nondisjunction of XX homologue
Found only in males, detected at
puberty
Incidence ---1 in 500 males
S/S:-
Sterility, testicular atrophy,
hyalinization of seminiferous
tubules, gynecomastia.